tbuckley/cabot-search huggingface dataset:
Relationships Between the Cumulative Incidences of Long-term Complications in Type 1 Diabetes: The DCCT/EDIC Study
Authors: Ionut Bebu, Barbara H. Braffett, Ian H. de Boer, Lloyd P. Aiello, John P. Bantle, Gayle M. Lorenzi, William H. Herman, Rose A. Gubitosi-Klug, Bruce A. Perkins, John M. Lachin, Mark E. Molitch
Journal: Diabetes Care (2022)

OBJECTIVE To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.
Losartan Decreases Incidence of Epilepsy in Arterial Hypertension
Authors: Anita Slomski
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Pan-cancer surveys indicate cell cycle-related roles of primate-specific genes in tumors and embryonic cerebrum
Authors: Chenyu Ma, Chunyan Li, Huijing Ma, Daqi Yu, Yufei Zhang, Dan Zhang, Tianhan Su, Jianmin Wu, Xiaoyue Wang, Li Zhang, Chun-Long Chen, Yong E. Zhang
Journal: Genome biology (2022)

Despite having been extensively studied, it remains largely unclear why humans bear a particularly high risk of cancer. The antagonistic pleiotropy hypothesis predicts that primate-specific genes (PSGs) tend to promote tumorigenesis, while the molecular atavism hypothesis predicts that PSGs involved in tumors may represent recently derived duplicates of unicellular genes. However, these predictions have not been tested.
Is There a Place for Temozolomide plus Nivolumab among Neuroendocrine Neoplasms?
Authors: Maria A. Velez, Edward B. Garon
Journal: Clinical Cancer Research (2022)

Immune checkpoint inhibitors have revolutionized the treatment of multiple solid malignancies, but their role in the treatment of neuroendocrine neoplasms (NEN) is unclear. The accompanying article reports on a study combining the programmed cell death (PD-1) inhibitor nivolumab with the alkylating agent temozolomide in patients with advanced NENs. See related article by Owen et al., p. 731.
Dysbiotic but nonpathogenic shift in the fecal mycobiota of patients with rheumatoid arthritis
Authors: Eun Ha Lee, Hyun Kim, Jung Hee Koh, Kwang Hyun Cha, Kiseok Keith Lee, Wan-Uk Kim, Cheol-Ho Pan, Yong-Hwan Lee
Journal: Gut Microbes (2022)

Rheumatoid arthritis (RA) is closely associated with the oral and gut microbiomes. Fungal cell wall components initiate inflammatory arthritis in mouse models. However, little is known regarding the role of the fungal community in the pathogenesis of RA. To evaluate the association between RA and the gut microbiome, investigations of bacterial and fungal communities in patients with RA are necessary. Therefore, we investigated the compositions and associations of fecal bacterial and fungal communities in 30 healthy controls and 99 patients with RA. The relative abundances of Bifidobacterium and Blautia decreased, whereas the relative abundance of Streptococcus increased, in patients with RA. The relative abundance of Candida in the fecal fungal community was higher in patients with RA than in healthy controls, while the relative abundance of Aspergillus was higher in healthy controls than in patients with RA. Candida species-specific gene amplification showed that C. albicans was the most abundant species of Candida. Ordination analysis and random forest classification models supported the findings of structural changes in bacterial and fungal communities. Aspergillus was the core fecal fungal genus in healthy controls, although Saccharomyces spp. are typically predominant in Western cohorts. In addition, bacterial–fungal association analyses showed that the hub node had shifted from fungi to bacteria in patients with RA. The finding of fungal dysbiosis in patients with RA suggests that fungi play critical roles in the fecal microbial communities and pathogenesis of RA.
Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus
Authors: Yu-Long Tang, Ai-Lin Liu, Su-Su Lv, Zi-Rui Zhou, Hong Cao, Shi-Jun Weng, Yu-Qiu Zhang
Journal: Science Translational Medicine (2022)

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light–mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino–ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)–positive neurons in the vLGN (vLGN Penk ). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGN Penk neurons. In addition, activation of the projections from vLGN Penk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGN Penk -DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.
Correction: Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)
Authors: John F.R. Robertson, Robert E. Coleman, Kwok-Leung Cheung, Abigail Evans, Chris Holcombe, Anthony Skene, Daniel Rea, Samreen Ahmed, Ali Jahan, Kieran Horgan, Petra Rauchhaus, Roberta Littleford, S.Y. Amy Cheung, Marie Cullberg, Elza C. de Bruin, Loumpiana Koulai, Justin P.O. Lindemann, Martin Pass, Paul Rugman, Gaia Schiavon, Rahul Deb, Pauline Finlay, Andrew Foxley, Julia M.W. Gee
Journal: Clinical Cancer Research (2022)

In the original version of this article (1), the values in Table 2B for Capivasertib 240 mg b.i.d
Pathogen genomics study of an early medieval community in Germany reveals extensive co-infections
Authors: Joanna H. Bonczarowska, Julian Susat, Barbara Mühlemann, Isabelle Jasch-Boley, Sebastian Brather, Benjamin Höke, Susanne Brather-Walter, Valerie Schoenenberg, Jonathan Scheschkewitz, Gabriele Graenert, Dirk Krausse, Michael Francken, Terry C. Jones, Joachim Wahl, Almut Nebel, Ben Krause-Kyora
Journal: Genome biology (2022)

The pathogen landscape in the Early European Middle Ages remains largely unexplored. Here, we perform a systematic pathogen screening of the rural community Lauchheim "Mittelhofen," in present-day Germany, dated to the Merovingian period, between fifth and eighth century CE. Skeletal remains of individuals were subjected to an ancient DNA metagenomic analysis. Genomes of the detected pathogens were reconstructed and analyzed phylogenetically.
Preterm infants at low risk for early-onset sepsis differ in early fecal microbiome assembly
Authors: Sagori Mukhopadhyay, Jung-Jin Lee, Erica Hartman, Emily Woodford, Miren B. Dhudasia, Lisa M. Mattei, Scott G. Daniel, Kelly C. Wade, Mark A. Underwood, Kyle Bittinger
Journal: Gut Microbes (2022)

Antibiotics are administered near-universally to very low birth weight (VLBW) infants after birth for suspected early-onset sepsis (EOS). We previously identified a phenotypic group of VLBW infants, referred to as low-risk for EOS (LRE), whose risk of EOS is low enough to avoid routine antibiotic initiation. In this cohort study, we compared 18 such infants with 30 infants categorized as non-LRE to determine if the lower risk of pathogen transmission at birth is accompanied by differences in microbiome acquisition and development. We did shotgun metagenomic sequencing of 361 fecal samples obtained serially. LRE infants had a higher human-to-bacterial DNA ratio than non-LRE infants in fecal samples on days 1–3 after birth, confirming lower bacterial acquisition among LRE infants. The microbial diversity and composition in samples from days 4–7 differed between the groups with a predominance of Staphylococcus epidermidis in LRE infants and Enterobacteriaceae sp. in non-LRE infants. Compositional differences were congruent with the distribution of virulence factors and antibiotic resistant genes. After the first week, the overall composition was similar, but changes in relative abundance for several taxa with increasing age differed between groups. Of the nine late-onset bacteremia episodes, eight occurred in non-LRE infants. Species isolated from the blood culture was detected in the pre-antibiotic fecal samples of the infant for all episodes, though these species were also found in infants without bacteremia. In conclusion, LRE infants present a distinct pattern of microbiome development that is aligned with their low risk for EOS. Further investigation to determine the impact of these differences on later outcomes such as late-onset bacteremia is warranted.
Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage
Authors: Sofia Ferreira-Gonzalez, Tak Yung Man, Hannah Esser, Rhona Aird, Alastair M. Kilpatrick, Daniel Rodrigo-Torres, Nicholas Younger, Lara Campana, Victoria L. Gadd, Benjamin Dwyer, Niya Aleksieva, Luke Boulter, Mark T. Macmillan, Yinmiao Wang, Katie J. Mylonas, David A. Ferenbach, Timothy J. Kendall, Wei-Yu Lu, Juan Carlos Acosta, Dominic Kurian, Stephen O’Neill, Gabriel C. Oniscu, Jesus M. Banales, Paul J. Krimpenfort, Stuart J. Forbes
Journal: Science Translational Medicine (2022)

Liver transplantation is the only curative option for patients with end-stage liver disease. Despite improvements in surgical techniques, nonanastomotic strictures (characterized by the progressive loss of biliary tract architecture) continue to occur after liver transplantation, negatively affecting liver function and frequently leading to graft loss and retransplantation. To study the biological effects of organ preservation before liver transplantation, we generated murine models that recapitulate liver procurement and static cold storage. In these models, we explored the response of cholangiocytes and hepatocytes to cold storage, focusing on responses that affect liver regeneration, including DNA damage, apoptosis, and cellular senescence. We show that biliary senescence was induced during organ retrieval and exacerbated during static cold storage, resulting in impaired biliary regeneration. We identified decoy receptor 2 (DCR2)–dependent responses in cholangiocytes and hepatocytes, which differentially affected the outcome of those populations during cold storage. Moreover, CRISPR-mediated DCR2 knockdown in vitro increased cholangiocyte proliferation and decreased cellular senescence but had the opposite effect in hepatocytes. Using the p21 KO model to inhibit senescence onset, we showed that biliary tract architecture was better preserved during cold storage. Similar results were achieved by administering senolytic ABT737 to mice before procurement. Last, we perfused senolytics into discarded human donor livers and showed that biliary architecture and regenerative capacities were better preserved. Our results indicate that cholangiocytes are susceptible to senescence and identify the use of senolytics and the combination of senotherapies and machine-perfusion preservation to prevent this phenotype and reduce the incidence of biliary injury after transplantation.
The path to venetoclax resistance is paved with mutations, metabolism, and more
Authors: Graeme P. Sullivan, Lyndsey Flanagan, Daniel Alencar Rodrigues, Tríona Ní Chonghaile
Journal: Science Translational Medicine (2022)

Venetoclax is a B cell lymphoma 2 (BCL-2)–selective antagonist used to treat chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). Although this has been a promising therapeutic option for these patients, many of these patients develop resistance and relapsed disease. Here, we summarize the emerging mechanisms of resistance to venetoclax treatment, discuss the promising combination strategies, and highlight the combinations that are currently in clinical trials. Efforts to understand mechanisms of resistance are critical to advance the development of new targeted therapeutic strategies and further our understanding of the biological functions of BCL-2 in tumor cells.
Therapy sculpts the complex interplay between cancer and the immune system during tumour evolution
Authors: Kerstin Thol, Piotr Pawlik, Nicholas McGranahan
Journal: Genome Medicine (2022)

Cancer development is an evolutionary process. A key selection pressure is exerted by therapy, one of the few players in cancer evolution that can be controlled. As such, an understanding of how treatment acts to sculpt the tumour and its microenvironment and how this influences a tumour's subsequent evolutionary trajectory is critical. In this review, we examine cancer evolution and intra-tumour heterogeneity in the context of therapy. We focus on how radiotherapy, chemotherapy and immunotherapy shape both tumour development and the environment in which tumours evolve and how resistance can develop or be selected for during treatment.
Brain Glucose Metabolism and Aging: A 5-Year Longitudinal Study in a Large Positron Emission Tomography Cohort
Authors: Kyoungjune Pak, Tuulia Malén, Severi Santavirta, Seunghyeon Shin, Hyun-Yeol Nam, Sven De Maeyer, Lauri Nummenmaa
Journal: Diabetes Care (2022)
<i>In Vivo</i>Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities
Authors: Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A. Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M. Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D. Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A. Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S. Davids, Gad Getz, Kenneth J. Livak, Ivana Bozic, Donna S. Neuberg, Ruben D. Carrasco, Catherine J. Wu
Journal: Blood Cancer Discovery (2022)

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease. This article is highlighted in the In This Issue feature, p. 101.
A B1a–natural IgG–neutrophil axis is impaired in viral- and steroid-associated aspergillosis
Authors: Nicole Sarden, Sarthak Sinha, Kyle G. Potts, Erwan Pernet, Carlos H. Hiroki, Mortaza F. Hassanabad, Angela P. Nguyen, Yuefei Lou, Raquel Farias, Brent W. Winston, Amy Bromley, Brendan D. Snarr, Amanda Z. Zucoloto, Graciela Andonegui, Daniel A. Muruve, Braedon McDonald, Donald C. Sheppard, Douglas J. Mahoney, Maziar Divangahi, Nicole Rosin, Jeff Biernaskie, Bryan G. Yipp
Journal: Science Translational Medicine (2022)

The lung naturally resists Aspergillus fumigatus ( Af ) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis—severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use—in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af -binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities.
The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location
Authors: Ilon Liu, Li Jiang, Erik R. Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia A. Hack, Daeun Jeong, McKenzie L. Shaw, Bernhard Englinger, Jenna LaBelle, Hafsa M. Mire, Sibylle Madlener, Lisa Mayr, Michael A. Quezada, Maria Trissal, Eshini Panditharatna, Kati J. Ernst, Jayne Vogelzang, Taylor A. Gatesman, Matthew E. Halbert, Hana Palova, Petra Pokorna, Jaroslav Sterba, Ondrej Slaby, Rene Geyeregger, Aaron Diaz, Izac J. Findlay, Matthew D. Dun, Adam Resnick, Mario L. Suvà, David T. W. Jones, Sameer Agnihotri, Jessica Svedlund, Carl Koschmann, Christine Haberler, Thomas Czech, Irene Slavc, Jennifer A. Cotter, Keith L. Ligon, Sanda Alexandrescu, W. K. Alfred Yung, Isabel Arrillaga-Romany, Johannes Gojo, Michelle Monje, Mats Nilsson, Mariella G. Filbin
Journal: Nature Genetics (2022)

Abstract Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
Long-term Intensive Blood Pressure Control Hard to Maintain
Authors: Anita Slomski
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal